Patient-specific modeling of individual sickle cell behavior under transient hypoxia

Abstract

Sickle cell disease (SCD) is a highly complex genetic blood disorder in which red blood cells (RBC) exhibit heterogeneous morphology changes and decreased deformability. We employ a kinetic model for cell morphological sickling that invokes parameters derived from patient-specific data. This model is used to investigate the dynamics of individual sickle cells in a capillary-like microenvironment in order to address various mechanisms associated with SCD. We show that all RBCs, both hypoxia-unaffected and hypoxia-affected ones, regularly pass through microgates under oxygenated state. However, the hypoxia-affected cells undergo sickling which significantly alters cell dynamics. In particular, the dense and rigid sickle RBCs are obstructed thereby clogging blood flow while the less dense and deformable ones are capable of circumnavigating dead (trapped) cells ahead of them by choosing a serpentine path. Informed by recent experiments involving microfluidics that provide in vitro quantitative information on cell dynamics under transient hypoxia conditions, we have performed detailed computational simulations of alterations to cell behavior in response to morphological changes and membrane stiffening. Our model reveals that SCD exhibits substantial heterogeneity even within a particular density-fractionated subpopulation. These findings provide unique insights into how individual sickle cells move through capillaries under transient hypoxic conditions, and offer novel possibilities for designing effective therapeutic interventions for SCD.

Synergistic Integration of Laboratory and Numerical Approaches in Studies of the Biomechanics of Diseased Red Blood Cells

“…Du et al [ 97 ] probed the deformability of SS-RBCs under transient hypoxia by using a high-throughput microfluidic device, where the kinetics of cell sickling and unsickling can be quantified (see Figure 3 (left)). Following this experimental study, Li et al [ 98 ] performed computational simulations of SS-RBCs with a broad spectrum of morphological and biomechanical alterations passing through capillary-like microchannels under transient hypoxia (see Figure 3 (right)). The authors found that SS-RBCs exhibit significant heterogeneity when passing through capillary-like microchannels even within a particular density group.…”

“…( Right ) The corresponding simulations of SS-RBCs passage through capillary-like microchannels under transient hypoxia by dissipative particle dynamics. Reproduced with permission from reference [ 98 ].…”

Bibliometric Analysis of Global Sickle Cell Disease Research From 1997 – 2017

“…This non-covalent polymerization of the sickle hemoglobin into long fibres under oxygen tension (deoxygenation) is the major pathological event in SCD. The resulting fibres distort red blood cells into atypical and heterogeneous shapes; crescent (classical sickle), elongated, granular and oval shapes [6,7,8] that lack deformability. These red cells with decreased deformability (loss of membrane elasticity) are rigid and sticky, and are usually trapped in narrow capillary blood vessels causing frequent episodes of vaso-occlusion and ischemia [6,9].…”

“…The resulting fibres distort red blood cells into atypical and heterogeneous shapes; crescent (classical sickle), elongated, granular and oval shapes [6,7,8] that lack deformability. These red cells with decreased deformability (loss of membrane elasticity) are rigid and sticky, and are usually trapped in narrow capillary blood vessels causing frequent episodes of vaso-occlusion and ischemia [6,9]. More so, the stiff cells that are unable to return to the normal shape are spotted and destroyed via hemolysis [9,10].…”

Modeling of biomechanics and biorheology of red blood cells in type-2 diabetes mellitus

“…-33). Two different particle-based RBC models using dissipative particle dynamics (DPD) (34,35), i.e., the one-component RBC models (36)(37)(38) and the two-component RBC models (39), have been developed and employed to conduct efficient simulations of RBCs in the microcirculation (40)(41)(42)(43)(44)(45)(46)(47)(48). In particular, the two-component RBC model, which considers the lipid bilayer and cytoskeleton separately but also includes the transmembrane proteins, facilitates detailed whole-cell exploration of the diverse biophysical and biomechanical aspects involving RBCs, such as probing the multiple stiffening effects of nanoscale knobs on malaria-infected RBCs (10,49), and predicting the biomechanical interactions between the lipid bilayer and the cytoskeleton in human RBCs (39,50).…”